Excessive O -GlcNAcylation Causes Heart Failure and Sudden Death

Background: Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes.O -GlcNAcylation (the attachment ofO -linked β-N-acetylglucosamine [O -GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels ofO -GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes:O -GlcNAc transferase (OGT) andO -GlcNAcase (OGA). Failing myocardium is marked by increasedO -GlcNAcylation, but whether excessiveO -GlcNAcylation contributes to cardiomyopathy and heart failure is unknown.Methods: We developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to controlO -GlcNAcylation independent of pathologic stress.Results: We found that OGT transgenic hearts showed increasedO -GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lowerO -GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardialO -GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I inO -GlcNAc–mediated cardiac pathology.Conclusions: Our data provide evidence that excessiveO -GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation ofO -GlcNAcylation is beneficial against pressure overload–induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessiveO -GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.